Patients with Pulmonary Metastases from Head and Neck Cancer Benefit from Pulmonary Metastasectomy, A Systematic Review

Background and Objectives: The incidence of distant metastases in patients with head and neck cancer (HNC) is approximately 10%. Pulmonary metastases are the most frequent distant location, with an incidence of 70–85%. The standard treatment options are chemo-, immuno- and radiotherapy. Despite a benefit for long-term survival for patients with isolated pulmonary metastases, pulmonary metastasectomy (PM) is not the treatment of choice. Furthermore, many otorhinolaryngologists are not sufficiently familiar with the concept of PM. This work reviews the recent studies of pulmonary metastatic HNC and the results after pulmonary metastasectomy. Materials and Methods: PubMed, Medline, Embase, and the Cochrane library were checked for the case series’ of patients undergoing metastasectomy with pulmonary metastases published since 1 January 2000. Results: We included the data of 15 studies of patients undergoing PM. The 5-year survival rates varied from 21% to 59%, with median survival from 10 to 77 months after PM. We could not identify one specific prognostic factor for long-term survival after surgery. However, at least most studies stated that PM should be planned if a complete (R0) resection is possible. Conclusions: PM showed reliable results and is supposedly the treatment of choice for patients with isolated pulmonary metastases. Patients not suitable for surgery may benefit from other non-surgical therapy. Every HNC patient with pulmonary metastases should be discussed in the multidisciplinary tumor board to optimize the therapy and the outcome.


Introduction
Head and neck cancer (HNC) is a generic term for carcinomas of the oral cavity, the tongue, the larynx, and the pharynx. HNCs are the ninth most common malignancy, with high mortality rates [1,2]. More than 90% of HNC are squamous cell carcinomas (SCC), 2 of 13 which originate from the epithelium of the mucosal lining of the upper aerodigestive tract [2]. The gold standard treatment for the management of these tumors is surgery, although radiotherapy, and other treatments play a role in the management of these conditions [3][4][5].
According to those studies, patients with pulmonary metastatic HNC undergoing PM tended to have better overall survival rates than patients receiving non-surgical therapy.
At least if PM is performed under specific criteria [46]: (1) The primary tumor needs to be treated curatively; (2) Distant metastases have to be ruled out with confidence; (3) R0 resection should be possible with adequate pulmonary reserve.

Objective
While PM is mentioned in the guidelines on HNC, no direct recommendations are given to otorhinolaryngologists for the specific treatment of pulmonary metastatic HNC [5,47,48]. However, many otorhinolaryngologists are not sufficiently familiar with the concept of PM. Therefore, we reviewed recent studies on pulmonary metastatic HNC and their results after pulmonary metastasectomy in order to identify independent factors, which could be used to stratify patients who could significantly benefit from PM compared to non-surgical therapy.

Study Inclusion and Exclusion Criteria
This systematic review followed the preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines [49]. PubMed, Medline, Embase, and the Cochrane library were queried for the case series' of patients undergoing metastasectomy with pulmonary metastases published since 1 January 2000.
Since the therapy in older studies sometimes deviates considerably from the current guidelines. Three independent investigators assessed study quality and bias risk (GS, PL, and SM-M).
The combination of the terms: (metastasectomy), (lung resection), (metastases), (pulmonary lesions), (head cancer), (head carcinoma), and (neck cancer and neck carcinoma) yielded 1036 results. Reviews and technical and pharmaceutical publications were excluded. In addition, we included publications in English and German with at least 20 surgically treated patients and metastasectomy as a curative approach.
We extracted data on patient population, resection type, status, method, postoperative complications, overall survival, recurrence rates, neo-adjuvant or adjuvant therapies, and long-term survival prognosis factors. The article selection process is depicted in Figure 1. were excluded. In addition, we included publications in English and German with at least 20 surgically treated patients and metastasectomy as a curative approach. We extracted data on patient population, resection type, status, method, postoperative complications, overall survival, recurrence rates, neo-adjuvant or adjuvant therapies, and long-term survival prognosis factors. The article selection process is depicted in Figure 1.

Long-Term Survival after Pulmonary Metastasectomy
The long-term survival rates after PM are presented in Table 2. Table 2. Long-term survival rates after PM.

The Importance of Tumor Histology
Most head and neck cancers are squamous cell carcinomas (HNSCC) [12]. Younes et al. showed the prognostic relevance of primary tumor histology. They demonstrated that patients with HNSCC showed significantly poorer long-term survival rates than those with adenocarcinoma (AC) [54]. Mochizuki [35]. Smoking is a predominant risk factor for HNC, as well as for lung cancer. Not surprisingly, patients with HNC have a three to six times higher probability of also developing concomitant lung cancer than the general population due to the overlap of risk factors [55]. Therefore, it is essential to differentiate pulmonary metastases from primary lung cancer from a treatment perspective. Approximately 5% of pulmonary metastases turn out to be primary lung cancer after pathological examination [35,56,57]. The histology of HNSCC and lung cancer are so similar that differentiation is not usually promising by regular histopathological examinations [57,58]. Thus, differentiation is only possible by molecular pathological examination [59]. These pathological examinations are complex and can only be performed in high-volume centers. One possibility is that the human papillomavirus (HPV) evidence might be proof of pulmonary metastases from HNC, since expressing the expression of HPV in lung cancer is rather unlikely [60,61]. Moreover, p53 measurements might also help to differentiate metastases from secondary solitary tumors.
Gender: The influence of gender as a prognostic factor is discussed and disputed in the literature. Shiono et al. showed that the male gender was an independent predictor of poor long-term survival after PM [36,37]. However, most included studies demonstrated that gender was not a prognostic factor for long-term survival [35,40,54].
Location of the primary tumor: Shiono et al. showed that the localization of the primary HNC was an independent risk factor for long-term survival [36]. They demonstrated that patients with metastatic HNC from the oral cavity had the poorest long-term survival rates [36]. Dudek et al. exhibited that primary tumor localization had no independent influence on the long-term prognosis [44].
Lymph node involvement: Shiono et al. demonstrated that intrathoracic lymph node affection was an independent risk factor for a shorter long-term survival [36]. No other study investigated intrathoracic lymph node affections independently.
Age: Yotsukura et al. demonstrated that old age was an independent risk factor for shorter long-term survival. According to the multivariate analysis, they demonstrated that patients > 70 years had a poorer prognosis [42].
Resection status: Winter et al. and Shiono et al. showed that R0 resection was a significant factor for long-term survival [35,37]. Nevertheless, Younes et al. reported no significant effect of a complete metastasectomy, but patients with R0 resection survived longer than with R1 or R2 resection (42.8 vs. 18.6 months) [54].

Discussion
Pulmonary metastasectomy is a reliable treatment for selected patients with isolated pulmonary metastatic head and neck cancer. However, not all patients are entirely suitable for surgery. For example, patients with other distant metastases, >3-5 pulmonary metastases, or inadequate pulmonary reserves may not be entirely suitable for PM. Multimodal therapy of metastatic HNC, therefore, includes chemo-and immunotherapy and checkpoint inhibitors, as well as radiation therapy, in addition to PM.

Medical Treatment
For decades, the only medical treatment option for patients with metastatic HNC was a platinum-based therapy [62,63]. Since immunotherapy and monoclonal antibodies were introduced for metastatic HNC patients in the mid-2000s, overall survival rates have been substantially prolonged [21,22,24,64]. Thus, it is clear that immunotherapy has also found its way into the guidelines for treating HNC [5]. Currently, there are different treatment options for metastatic HNC depending on the patients' targets and physical condition [5]. One of the first-line therapy options is the EXTREME regimen consisting of chemotherapy (platinum-based and fluorouracil) combined with the monoclonal antibody cetuximab [24,25,65]. The EXTREME regimen is replaced by the more effective and bettertolerated TPex regimen as first-line therapy (docetaxel-platinum-cetuximab) [26,66,67]. Moreover, there is the fully human IgG4 PD-1 inhibitor nivolumab, which restores antitumor immunity. According to the latest guidelines, nivolumab is mainly used for local recurrence and less for treating distant metastases [21,64]. Nivolumab is currently the second-line therapy after pembrolizumab + platinum-based, the EXTREME regimen, and TPex regimen.
The high discrepancy in survival rates between patients after PM and patients receiving medical treatment is not the least since patients subjected to immunotherapy could no longer undergo PM for several reasons. These include the number or the size of the metastases, extrapulmonary metastases, and if patients are not suitable for PM due to their inadequate pulmonary reserve.

Radiation Therapy
Radiation therapy is now available for decades as a supplemental or alternative therapy stereotactic body radiation (SBRT) and is frequently regarded as an option in cases with arguments against surgery including compromised physical condition, unfavorable central location pulmonary nodule, or previous PM [27][28][29][30]. Ricco

The Surgical Treatment of Pulmonary Metastases
Although survival improved due to modern immunotherapy, it should be considered that patients with isolated pulmonary metastases may benefit substantially from pulmonary metastasectomy. Stereotactic body radiation should also be considered an option in cases with arguments against PM [27]. A significant advantage of PM over SBRT is that surgery allows histological material to be obtained.
PM should only be considered if a complete (R0) resection is within the realm of possibility [35,37], if less than three pulmonary metastases are diagnosed [38,54] if the lesion size is smaller than 1.4 cm [43,44], and if there are only unilateral metastases [35]. Several studies indicated that a longer DFI resulted in a longer overall survival after PM [42,43,54]. There are several reasons why patients with a longer DFI benefit more from PM. It can be speculated that HNC patients with a longer DFI tend to have a less aggressive primary tumor [38,45]. These differences in DFI are not the least due to the different histology. Patients with SCC tend to have shorter DFI than patients with histological evidence of adenocarcinoma or adenoid cystic carcinoma. Furthermore, the timing of surgery for the primary HNC significantly impacts the DFI. Nevertheless, patients with a shorter DFI should also be subjected to PM. Nevertheless, patients with a shorter DFI should also be subjected to PM [34,70]. The most commonly used procedure for pulmonary metastasectomy is sublobar resection. It is well accepted as an appropriate procedure because of its reduced invasiveness and ability to preserve lung tissue while maintaining a sufficient safety distance. Anatomical resections, such as segmentectomy or even lobectomy, provide radicality and might be an option based on the size and localization of the pulmonary lesions but at the cost of healthy lung parenchyma. However, pneumonectomy should be excluded from the therapy, due to its 5-10% rate of serious perioperative complications and its high rate of postoperative morbidity [71]. Surgeons have the option of a thoracotomy or minimally invasive approaches via VATS and, more recently, robotic-assisted thoracic surgery (RATS). The advantage of lateral thoracotomy is a clear view of the operating field. Furthermore, entire manual palpation of the lung is feasible. Hence, a digital detection of metastases that remained invisible in previous CT scans might be possible [39,[72][73][74]. Conversely, VATS has lower complication rates and a lower operative trauma. Furthermore, VATS may provide superior cosmetic results and earlier discharge from the hospital. In recent years, RATS has also become increasingly established in thoracic surgery [75]. RATS provides a three-dimensional view for the surgeon and only requires exceedingly tiny incisions for the surgical approach. Therefore, the advantages of lateral thoracotomy can almost be combined with the advantages of VATS. However, many hospitals are not yet equipped with robotic devices, so this approach is not yet feasible for every department [76][77][78]. As with all malignancies, HNC patients may also develop recurrent pulmonary metastases months or years after PM. For this reason, active surveillance, in addition to the tumor follow-up of the primary HNC, should be implemented within the first two years after PM. The appropriate screening method for pulmonary metastases are CT-scans of the thorax at six-month intervals within the first 24 months [13]. In addition to imaging techniques, an analysis of tumor markers could provide information about recurrences. Hundsdorfer et al. analyzed tumor markers in the context of an SCC of the oral cavity [79]. Patients with elevated "uPA" (urokinase-type plasminogen activator, threshold: 4.58 ng/mg protein) and elevated "PAI-1" (plasminogen activator inhibitor type 1, threshold: 106.3 ng/mg protein) levels were more likely to develop recurrences [79]. If patients develop recurrent ipsilateral pulmonary metastases, redo PM could provide overall survival benefits [50][51][52][53], naturally associated with the increased mortality and morbidity risks of a redo operation. Nevertheless, this procedure usually is quite tolerable for patients.

Which Therapy for Which Patient?
Despite significant advances in treating metastatic head and neck cancer in recent years, the overall survival remains poor. The median survival of patients undergoing pulmonary metastasectomy was 10-77 months [31][32][33][34][35][36][37][39][40][41][42][43][44][45]54]. The median survival of patients after immunotherapy was 7-10 months [21][22][23]25]. There is a wide variation in survival rates between studies. As already described, this is due to various reasons, such as the histology of the primary tumors. In addition, another confounding factor is the surgery performed. In the work of Mochizuki et al., for example, patients who underwent pneumonectomy were also included [31]. This is an operation that should not be performed because the mortality and morbidity are out of proportion to the benefit for the patient [71].
However, patients receiving non-surgical therapy are vastly different. Those patients usually are unsuited to undergo PM due to many distant metastases. Ferris et al. treated patients with tumor progression or recurrence within six months with nivolumab, regardless of the number or the size of the metastases [21]. Cohen et al. and Vermorken et al. used the same criteria in treating patients with pembrolizumab and Cetuximab, respectively [23,25]. Guigay et al. treated all patients with the TPex regimen regardless of the localization of the distant metastases [26].
In order to decide which patient might benefit from which therapy, all HNC patients with pulmonary metastases should always be discussed in the MDT comprising of thoracic surgeons, otorhinolaryngologists, medical oncologists, radiologists, pathologists, and other clinicians.

Conclusions
Patients with pulmonary metastatic head and neck cancer achieved an average survival rate between 10 to 77 months after pulmonary metastasectomy. However, only patients with isolated pulmonary metastases benefit from pulmonary metastasectomy. Patients with distant metastases, multiple bilateral pulmonary metastases, or inadequate pulmonary reserve may benefit from chemo-or immunotherapy, checkpoint inhibitors, radiotherapy, or stereotactic body radiation but with shorter overall survival rates. More studies, particularly randomized control trials, are needed to stratify the patient population further. In conclusion, every patient with pulmonary metastatic head and neck cancer should be carefully staged and discussed in the MDT to optimize therapy and outcomes.  Data Availability Statement: The data underlying this article will be shared on reasonable request to the corresponding author.

Conflicts of Interest:
The authors declare no conflict of interest.